A drug delivery system has been developed for the purpose of efficiently delivering an appropriate amount of a drug to a site with a disorder. For the purpose of adopting to individual purpose or disorder, a variety of the systems have been studied; for example, a controlled drug-release preparation using as a carrier a hydrophobic polymer material, which is non-degradable after administered into the living body. As a method of controlling release of a drug from such preparation, one using an additive such as an albumin (Japanese Patent publication (Tokkohei) No. 61959/1995), and one forming an outer layer consisting of hydrophobic polymer alone (Japanese Patent publication (Tokkaihei) No. 187994/1995) are disclosed. However, when a preparation contains several drugs, it is not possible to control the release of the drugs, by those techniques, so that each drug is released at a desired behavior from the preparation. The reasons thereof are as follows:
When a drug, of which release is to be controlled, is water-soluble, the powdery drug does not dissolve in a carrier but exists in a dispersed state therein. When such preparation is put in aqueous surroundings, the powdery drug present on the surface of the preparation dissolves in the surrounding water, and is released. Then, powdery drug present around a hole thus-formed dissolves to be released. Repetition of such phenomenon results in formation of a channel whereby the drug in the inside of the preparation is sequentially released. Thus, the drug-release behavior is influenced by physical features such as solubility or diffusion rate of drug into the aqueous surroundings. Accordingly, in a preparation wherein several drugs are homogeneously dispersed into a single carrier, it is impossible to respectively control the release of each drug as desired because the drug-release is influenced only by the physical features of the drugs.
Japanese Patent Publication (Tokkohei) No. 78017/1995 discloses a pulsatively controlled release preparation, which is designed so as to intermittently release one or more drugs. In this preparation, it is possible to control so that each drug is released at a different period of time, but not to separately control the release of several drugs during the same period of time. For some diseases, it will be more effective to release one or more drugs with a different behavior. However, as stated above it has never been achieved by a single preparation.
On the other hand, U.S. Pat. No. 4,351,337 discloses a biodegradable preparation with multi-layer structure wherein a poly-amino acid, which degrades by an enzyme in the living body, is used as a carrier, and wherein the drug is released by diffusion and degradation of a carrier. Accordingly, such biodegradable preparation with multi-layer structure has a problem, for example enzymes in the living body may influence its drug-release behavior.
Problem to be Solved by the Invention
The present invention has been done from the standpoint as stated above. An object of the present invention is to provide a preparation which can release two or more drugs separately at appropriate rates depending on disease or a preparation where the release behaviors of one or more drugs can be precisely controlled. Said problem to be solved has also been found by the inventors.
The Means to Solve the Problem
The inventors have eagerly studied for solving the problem and found that the followings are an essential key in releasing one or more drugs with different behavior: to form an implantable rod-like preparation in multi-layer structure, and to design it so that each layer is adapted to the most suitable arrangement and structure. In addition, by using as a carrier a biologically non-degradable hydrophobic polymer which does not degrade in vivo and is not influenced by enzyme etc., the preparation of the present invention can release stably the drug in vivo.
Thus, the present invention includes the following embodiments.
(1) A preparation which comprises an outer layer wherein a water-soluble drug is dispersed in a carrier comprising a biologically non-degradable hydrophobic polymer material, and one or more inner layer(s) wherein a water-soluble drug, which is different or different in concentration thereof from the drug contained in the outer layer, is dispersed in a carrier comprising a biologically non-degradable hydrophobic polymer material, and in which the outer and inner layer(s) are concentrically located in diametral direction of the rod-like preparation and both or one of the ends in the axial direction are open so as to directly come into contact with the environment.(2) A preparation as stated in item (1) wherein a layer consisting of only biologically non-degradable hydrophobic polymer material exists between the inner layer in which a water-soluble drug is dispersed and the outer layer, or between two inner layers in which a water-soluble drug is dispersed.(3) A preparation as stated in item (1) or (2) wherein each layer contains a different water-soluble drug.(4) A preparation as stated in item (1) or (2) wherein each layer contains a different concentration of the same water-soluble drug.(5) A preparation as stated in any one of items (1)–(4) wherein at least one of the outer layer or inner layer(s) contains two or more drugs.(6) A preparation as stated in any one of items (1)–(5) wherein the biologically non-degradable hydrophobic polymer material is silicone.